Acute on chronic bilateral renal vein thrombosis in the setting of remission of class V lupus nephritis: A case report and literature review

Renal vein thrombosis (RVT), defined as the presence of a thrombus in the major renal vein or one of its tributaries, can present acutely or go unnoticed resulting in acute kidney injury or chronic kidney disease. RVT is associated with multiple etiologies, including nephrotic syndrome, thrombophilia, autoimmune disorders, and malignancy. Patients with systemic lupus erythematosus (SLE), a multiorgan autoimmune disorder, are predisposed to coagulopathy and thus are at a higher risk of venous and arterial thromboembolism. We describe the case of a 41-year-old man with SLE and biopsy-proven membranous glomerulonephritis (WHO class V lupus nephritis) in clinical remission with no evidence of nephrotic range proteinuria who presented with macroscopic hematuria and was diagnosed with acute-on-chronic bilateral RVT. We discuss the different causes of RVT and compare the clinical presentation, diagnostic imaging findings, and management of acute and chronic RVT.


Introduction
Renal vein thrombosis (RVT), the presence of a thrombus in the major renal vein or one of its tributaries, can present acutely or go unnoticed due to lack of symptoms resulting in acute kidney injury or chronic citation El Mouhayyar C, Segal C, Jaber BL, Balakrishnan VS. Acute on chronic bilateral renal vein thrombosis in the setting of remission of class V lupus nephritis: A case report and literature review.
Clin Nephrol Case Studies. 2023; 11: 39-43. DOI 10.5414/CNCS110922 kidney disease. In the 1840s, Rayer, a French nephrologist, was the first to describe RVT and its association with proteinuria [1]. RVT is more commonly seen in men with no racial predilection, and almost two third present with bilateral renal vein involvement [1]. RVT is associated with multiple etiologies, including nephrotic syndrome, thrombophilia, autoimmune disorders, and malignancy. Systemic lupus erythematosus (SLE) is a multiorgan autoimmune disorder characterized by a broad spectrum of clinical manifestations and serological findings. Patients with SLE are predisposed to coagulopathy and thus are at a higher risk of venous and arterial thromboembolism [2].
We present the case of a 41-year-old man with SLE and biopsy-proven membranous glomerulonephritis (World Health Organization (WHO) class V lupus nephritis) in clinical remission with no evidence of nephrotic range proteinuria presenting with macroscopic hematuria and found to have bilateral acute-on-chronic RVT.

Case presentation
A 41-year-old man with SLE and biopsyproven membranous glomerulonephritis (WHO class V lupus nephritis) diagnosed 2.5 years earlier, maintained on mycophenolate mofetil (1,000 mg twice daily), prednisone (5 mg daily), and hydroxychloroquine (200 mg daily), hypertension, and hypothyroidism presented to the hospital with bilateral flank pain of 1 month duration, gross hematuria for 2 days, and nausea and vomiting for 1 day. He was afebrile with a normal heart rate of 71 beats/minute. He was hypertensive with a blood pressure of 172/110 mmHg and oxygen saturation was 100% on room air. On physical examination, there was mild diffuse abdominal tenderness but no costovertebral angle tenderness, and trace lower extremity edema. At initial presentation, the white blood cell count was elevated at 13,000/μL. C-reactive protein level was elevated at 0.81 mg/dL (normal level, < 0.5), and LDH was elevated at 313 U/L (range, 102 -266). Initial serum creatinine was 1.4 mg/dL with serum potassium of 2.9 mEq/L and serum albumin of 4.4 g/dL. Random urine total proteinto-creatinine ratio was 300 mg/g and random urine albumin-to-creatinine ratio was 81 mg/g. Of note, 9 months prior to presentation, serum creatinine was 1.1 mg/dL with an estimated glomerular filtration rate (GFR) of 83 mL/minute/1.73m 2 , and random urine total protein-to-creatinine ratio was 691 mg/g. A nasal swab SARS-CoV-2 nucleic acid amplification test was negative. His lipid profile was unremarkable, with a total cholesterol of 95 mg/dL and an LDL cholesterol of 42 mg/dL. Non-contrast computed tomography (CT) scan revealed enlarged kidneys bilaterally, more prominent on the right, with bilateral perinephric edema. There was significant narrowing of the renal veins bilaterally, and numerous venous collaterals in the perinephric space suggestive of bilateral RVT. Increased density in the left renal pelvis and bladder were suggestive of hemorrhage within the collecting system. He was initiated on systemic anticoagulation with a continuous infusion of unfractionated heparin, and a Foley catheter was inserted with continuous bladder irrigation.
The patient developed acute kidney injury, and his serum creatinine peaked at 1.9 mg/dL in the first 48 hours of hospitalization. An extensive workup for thrombophilia was undertaken and was inconclusive. Prothrombin time, partial thromboplastin time, and fibrinogen level were normal. Functional protein S was 86% (normal range, 63 -140%), and functional protein C was 72% (normal range, 73 -180%). Anti-thrombin III activity was 86% (normal range, 75 -135%). Factor V Leiden mutation as well as prothrombin G20210A mutation were absent. Serum homocysteine level was mildly elevated at 15.2 μmol/L (normal range, < 13.0). Antinuclear antibodies screening test was positive, but the anti-double-stranded DNA antibody titer was undetectable. Levels of complement components C3 and C4 were normal. Rheumatoid factor and anti-Smith antibody titer were undetected. Antineutrophil cytoplasmic antibody titers, including anti-myeloperoxidase and anti-proteinase-3  antibody titers, were undetected. The anti-RNP (ribonucleoproteins) antibody titer was elevated at 3.9 AI (normal value, < 0.9). Anti-phospholipid autoantibodies were undetectable, specifically, anti-cardiolipin IgA, IgG, and IgM antibody titers, and anti-β-2 glycoprotein-I IgA, IgG, and IgM antibody titers. Lupus anticoagulant screen was negative.
Magnetic resonance venography (MRV) (Figure 1) revealed markedly narrowed bilateral renal veins with poor contrast opacification. No obvious acute RVT was identified, and the appearance of the study suggested a more chronic process, possibly with chronic thrombosis, or scarring from chronic thrombosis, particularly due to the extent of perinephric collateral veins. A CT venogram was suggested to improve the spatial reso-lution provided by CT and to evaluate for acute thrombus. After pre-hydration with 1 L of normal saline, the patient underwent a contrast-enhanced CT of the abdomen (Figure 2), which demonstrated filling defects in the renal veins bilaterally consistent with acute thrombus and marked attenuation of the distal left renal vein.
During hospitalization, the kidney function progressively normalized with a drop in serum creatinine to 0.95 mg/dL, and hematuria resolved. The patient was discharged on warfarin therapy (with an international normalized ratio (INR) target of 2 -3) and his immunosuppressive medications. Three months following hospital discharge, the patient had no recurrence of gross hematuria, serum creatinine was normal at 0.95 mg/dL, complement levels remained normal, and  anti-double-stranded DNA antibody titer undetected.

Discussion
RVT can present acutely or can be chronic in nature. Acute RVT usually presents with symptoms of flank pain and tenderness, worsening kidney function, proteinuria and hematuria, and is most often due to a hypercoagulable state [2]. By contrast, chronic RVT is usually asymptomatic or insidious in onset, and may rarely present with peripheral edema or be identified during a workup for another culprit such as pulmonary embolism [2,3]. Interestingly, our patient's symptoms were acute as he had flank pain for almost a month and gross hematuria for 2 days. However, the imaging findings revealed bilateral renal veins of small caliber with perinephric collateral veins suggesting chronicity and raising the possibility of acute-on-chronic RVT (Table 1).
Hypercoagulability, commonly seen with active nephrotic syndrome, especially membranous glomerulonephritis, typically with serum albumin less than 2.8 gm/dL, is associated with a higher risk of RVT [4]. It appears to be related to urinary loss of anti-coagulation factors such as antithrombin III, plasminogen, and protein C and S. Our patient did not have proteinuria, his serum albumin was normal at 4.4 gm/dL, and activity of these coagulation factors was within the normal range. Other common causes of hypercoagulability include factor V Leiden mutation, prothrombin G20210A mutation as well as antiphospholipid syndrome. However, our patient's anti-cardiolipin antibody and anti-β-2 glycoprotein-I antibody titers were undetectable, and the lupus anticoagulant screen was negative. He also did not carry the factor V Leiden or prothrombin G20210A mutation.
Dyslipidemia plays a role in accelerating atherosclerosis and thus might have a causative role in the increased risk of thrombosis seen in nephrotic syndrome [5]. However, our patient's lipid profile was within normal limits making dyslipidemia less likely an inciting factor.
Renal malignancy, especially renal cell carcinoma that extends into the renal veins, is also associated with RVT most likely by extrinsic compression of the renal vein [6]. This can be also seen with enlarged retroperitoneal lymphadenopathy, an abdominal aortic aneurysm, or a retroperitoneal tumor compressing the renal vein or inferior vena cava. However, abdominal imaging in our patient did not show any evidence of malignancy, aortic aneurysm, or lymphadenopathy making this less likely.
Renal vein thrombosis in the setting of lupus nephritis is more commonly associated with lupus membranous glomerulonephritis as well as the antiphospholipid syndrome [7]. Anti-double-stranded DNA antibody titers and complement levels closely correlate with disease activity in lupus nephritis [8,9]. Our patient's complement levels were normal, anti-double-stranded DNA antibody titer undetectable, lupus membranous glomerulonephritis well controlled on immunosuppressive medications with no active flare on presentation, and his nephrotic syndrome was in remission.
Although anti-RNP antibodies are detectable in 25 -40% of patients with SLE [10], these autoantibodies are not specific to SLE and can be found in other rheumatological disorders. High titers of anti-RNP antibodies are considered as a classification criterion for mixed connective tissue disease (MCTD) with a high sensitivity but low specificity [10]. Unlike other autoantibodies, anti-RNP antibodies do not correlate with disease activity. Our patient had a mildly elevated anti-RNP antibody titer, which is of unclear significance, as he did not have any other presenting features that meet the criteria for MCTD.
In conclusion, RVT is caused by a multitude of conditions and can present either acutely or go unnoticed thus inducing acute or chronic kidney disease. In this case report, we present a patient with acute-on-chronic RVT and discuss the clinical presentation, diagnosis, and treatment modalities.

Funding
The authors were not the recipients of any internal or external funding for this work.

Conflict of interest
The authors declare no conflict of interest or funding pertaining to this manuscript.
citation El Mouhayyar C, Segal C, Jaber BL, Balakrishnan VS. Acute on chronic bilateral renal vein thrombosis in the setting of remission of class V lupus nephritis: A case report and literature review.